Center for Drug Safety and Evaluation Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Mutat Res. 2012 Mar 18;743(1-2):52-8. doi: 10.1016/j.mrgentox.2011.12.021. Epub 2012 Jan 5.
Aristolochic acid (AA) is known to be a potent mutagen and carcinogen. Aristolochic acid I (AAI) and aristolochic acid II (AAII), the two major components of AA, differ from each other by a single methoxy group. However, their individual mutagenic characteristics in vivo are unclear. In the present study, we compared their DNA adduct formation and mutagenicities in the gpt delta transgenic mouse kidney. The dA-AAI, dG-AAI, dA-AAII and dG-AAII were identified in the kidney two days after intragastric administration of AAI or AAII at 5mg/kg. The concentration of DNA adducts formed by AAII was approximately 2.5-fold higher than that formed by AAI (p<0.05). The mutant frequency induced by AAII was nearly two-fold higher than that induced by AAI (p<0.05) following administration of 5mg/kg AAI or AAII, five times per week for six weeks. Investigation of the mutation spectra showed no statistically significant difference between AAI- and AAII-treated mice (p>0.05). A:T to T:A transversion was the predominant type of mutation in both treated groups, the GC-associated mutation rates, however, differed between the AAI and AAII treatments. The in vivo metabolic pathways of AAI and AAII are different, and this may affect their mutagenicity. In the present study, we measured the levels of AAI and AAII in the kidney and plasma of gpt delta transgenic mice at multiple time points after a single intragastric dose of 1 or 5mg/kg of either component. Our results showed that the levels of AAII in both kidney and plasma were considerably higher than those of AAI (p<0.01). The present study indicated that AAII showed more carcinogenic risk than AAI in vivo, and this may be, at least partly, the result of its increased levels in kidney and plasma.
马兜铃酸（AA）已知是一种强诱变剂和致癌剂。马兜铃酸 I（AAI）和马兜铃酸 II（AAII）是 AA 的两个主要成分，它们之间仅相差一个甲氧基。然而，它们在体内的单独诱变特征尚不清楚。在本研究中，我们比较了它们在 gpt delta 转基因小鼠肾脏中的 DNA 加合物形成和致突变性。在以 5mg/kg 灌胃给予 AAI 或 AAII 两天后，在肾脏中鉴定出了 dA-AAI、dG-AAI、dA-AAII 和 dG-AAII。AAII 形成的 DNA 加合物浓度约为 AAI 的 2.5 倍（p<0.05）。在给予 5mg/kg AAI 或 AAII，每周 5 次，共 6 周后，AAII 诱导的突变频率几乎是 AAI 的两倍（p<0.05）。突变谱的研究表明，AAI 和 AAII 处理的小鼠之间没有统计学上的显著差异（p>0.05）。A:T 到 T:A 颠换是两个处理组中主要的突变类型，然而，GC 相关的突变率在 AAI 和 AAII 处理之间有所不同。AAI 和 AAII 的体内代谢途径不同，这可能会影响它们的致突变性。在本研究中，我们在单次灌胃给予 1 或 5mg/kg 任一成分后，在多个时间点测量了 gpt delta 转基因小鼠肾脏和血浆中的 AAI 和 AAII 水平。我们的结果表明，AAII 在肾脏和血浆中的水平均明显高于 AAI（p<0.01）。本研究表明，AAII 在体内比 AAI 具有更高的致癌风险，这至少部分是由于其在肾脏和血浆中的水平升高所致。
